The exact mechanism by which SPE B inhibits neutrophil phagocytosis has yet to be clearly defined. A speB mutant strain has decreased resistance to neutrophil phagocytosis, dissemination to organs, and mortality in the mouse model ( 26, 28, 30, 31, 32). SPE B digests a number of host proteins, including immunoglobulin ( 8, 10, 14, 45), kininogen ( 17), matrix metalloprotease ( 3), urokinase receptor ( 51), fibrinogen ( 33), and fibronectin as well as vitronectin ( 25) and interleukin-1 precursor ( 24). Patients with lower antibody levels against SPE B are more likely to succumb to invasive GAS disease ( 15). Clinical investigations indicate that high levels of SPE B protease activity are significantly associated with signs of streptococcal toxic shock syndrome and with mortality ( 19). Several reports suggest that SPE B, a cysteine protease, may be a critical virulence factor in streptococcal infections. Furthermore, GAS secretes DNases to degrade the neutrophil extracellular trap, which functions as an extracellular bactericidal weapon of neutrophils, thereby evading the innate immune response ( 43). pyogenes)/Mac (group A streptococcal Mac-1-like protein), streptococcal pyrogenic exotoxin B (SPE B), and endo-β- N-acetylglucosaminidase (EndoS), which are able to bind or cleave IgG and inhibit opsonophagocytosis ( 8, 9, 10, 12, 14, 29, 45, 46).
Moreover, GAS also secretes several exotoxins and enzymes, such as IdeS (immunoglobulin G -degrading enzyme of S. Another GAS protective mechanism involves membrane attack complex inhibition ( 16) and resistance to neutrophil phagocytosis ( 47) through secretion of streptococcal inhibitor of complement. Also, GAS expresses C5a peptidase to digest C5a and inhibit recruitment of neutrophils to sites of infection ( 22). Unlike M protein, both the hyaluronic acid capsule and collagen recruitment of GAS form the physical barrier on the bacterial surface to avoid complement opsonization and phagocytosis by neutrophils ( 47). The surface M and M-like proteins of GAS avoid opsonization by complement- and phagocytosis-mediated killing, in part by binding to complement regulatory proteins, such as C4b-binding protein, factor H, and factor H-like protein ( 2, 23). Several mechanisms by which GAS evades the innate immunity have been described ( 21, 47). Despite intensive care with antimicrobial therapy, the mortality has remained high for these infections and postinfection sequelae, such as acute rheumatic fever ( 47). Group A streptococcus (GAS Streptococcus pyogenes) is an important human pathogen that causes a variety of infections, including pharyngitis, impetigo, cellulitis, necrotizing fasciitis, puerperal sepsis, and streptococcal toxic shock syndrome ( 11, 41, 42). These results suggest a novel SPE B mechanism, one which degrades serum C3 and enables GAS to resist complement damage and opsonophagocytosis. A20 opsonized with SPE B-treated serum was more resistant to neutrophil killing than A20 opsonized with normal serum, and SPE B-mediated resistance was C3 dependent. Moreover, the amount of C3 fragments on the A20 cell surface, a SPE B-producing strain, was less than that on its isogenic mutant strain, SW507, after opsonization with normal serum. SPE B-treated, but not C192S-treated, serum also impaired opsonization of C3 fragments on the surface of GAS strain A20. Reconstitution of C3 into SPE B-treated serum unblocked zymosan-mediated neutrophil activation dose dependently. Further study showed that cleavage of serum C3 by SPE B, but not C192S, blocked zymosan-induced production of reactive oxygen species in neutrophils as a result of decreased deposition of C3 fragments on the zymosan surface. In contrast, C192S, a SPE B mutant lacking protease activity, had no effect on complement activation. Using an enzyme-linked immunosorbent assay, we found that SPE B-treated serum impaired the activation of the classical, the lectin, and the alternative complement pathways.
In this study, we examined the mechanism SPE B uses to enable bacteria to resist opsonophagocytosis. The inhibition of phagocytic activity by SPE B may help prevent bacteria from being ingested. Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcus (GAS) infection.
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